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SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer. SAFFRON-104:一项针对晚期肝细胞癌和胃癌/胃食管交界处癌的西曲替尼单药或联合替赛珠单抗的Ib/II期研究。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1007/s00262-024-03806-2
Jin Li, Yuxian Bai, Zhendong Chen, Jieer Ying, Yabing Guo, Weijia Fang, Feng Zhang, Jianping Xiong, Tao Zhang, Zhiqiang Meng, Jingdong Zhang, Zhenggang Ren, Chunyi Hao, Yajin Chen, Xiaoyan Lin, Hongming Pan, Fuxiang Zhou, Xin Li, Fan Yu, Juan Zhang, Zhang Zhang, Shukui Qin

Background: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC).

Methods: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II).

Results: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC.

Conclusions: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

背景介绍西曲拉替尼是一种谱系选择性酪氨酸激酶抑制剂,靶向TAM(TYRO3、AXL、MER)、VEGFR-2、KIT和MET。SAFFRON-104(NCT03941873)是一项多队列Ib/II期研究,研究对象是晚期肝细胞癌(HCC)或胃癌/胃食管交界处癌(GC/GEJC)患者,研究方法是西曲替尼联合/不联合抗程序性细胞死亡蛋白1(PD-1)抗体tislelizumab:符合条件的患者均为组织学/细胞学确诊的晚期HCC或GC/GEJC。I期确定了西曲拉替尼联合/不联合替赛珠单抗的II期推荐剂量(RP2D)。II期评估了西曲拉替尼单药治疗预处理HCC患者,以及西曲拉替尼联合替赛珠单抗治疗抗PD-(L)1-naï或治疗HCC和抗PD-(L)1-naïGC/GEJC患者。主要终点是安全性/耐受性(I期)和客观应答率(ORR)(II期):截至数据截止日(2023 年 3 月 31 日),共有 111 例患者入组,其中 102 例疗效有效(中位随访时间为 9.1 个月 [范围:0.7-36.9])。西曲拉替尼的RP2D被确定为120毫克,每天口服一次。在接受西曲拉替尼单药治疗和西曲拉替尼联合替赛珠单抗治疗的患者中,分别有14名(51.9%)和42名(50.0%)患者发生了≥3级的治疗相关不良事件。接受西曲替尼单药治疗的HCC预处理患者的ORR为25%(95%置信区间[CI]:8.7-49.1)。在接受西曲替尼联合替赛利珠单抗治疗的患者中,抗PD-(L)1-无效的HCC患者的ORR为11.5%(95% CI 2.4-30.2),抗PD-(L)1-治疗的HCC患者的ORR为9.5%(95% CI 1.2-30.4),抗PD-(L)1-无效的GC/GEJC患者的ORR为16.1%(95% CI 5.5-33.7):在晚期HCC和GC/GEJC患者中,西曲拉替尼联合/不联合替赛珠单抗的耐受性普遍良好,并显示出初步的抗肿瘤活性。
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引用次数: 0
Characterization of pre- and on-treatment soluble immune mediators and the tumor microenvironment in NSCLC patients receiving PD-1/L1 inhibitor monotherapy. 接受 PD-1/L1 抑制剂单药治疗的 NSCLC 患者治疗前和治疗中可溶性免疫介质及肿瘤微环境的特征。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1007/s00262-024-03781-8
Daiki Murata, Koichi Azuma, Kenta Murotani, Akihiko Kawahara, Yuuya Nishii, Takaaki Tokito, Tetsuro Sasada, Tomoaki Hoshino

Background: Despite the favorable therapeutic efficacy observed with ICI monotherapy, the majority of non-small cell lung cancer (NSCLC) patients do not respond. Therefore, identifying patients who could optimally benefit from ICI treatment remains a challenge.

Methods: Among 183 patients with advanced or recurrent NSCLC who received ICI monotherapy, we analyzed 110 patients whose pre- and post-treatment plasma samples were available. Seventy-three soluble immune mediators were measured at ICI initiation and 6 weeks later. To identify useful biomarkers, we analyzed the association of pre-treatment levels and on-treatment changes of soluble immune mediators with survival of patients. The associations of pre-treatment or on-treatment biomarkers with irAE development, PD-L1 expression, CD8+ TIL density, and neutrophil to lymphocyte ratio (NLR) were also analyzed.

Results: Univariate analysis showed that pre-treatment biomarkers included 6 immune mediators, whereas on-treatment biomarkers included 8 immune mediators. Multivariate analysis showed that pre-treatment biomarkers included 4 immune mediators (CCL19, CCL21, CXCL5, CXCL10), whereas on-treatment biomarkers included 5 immune mediators (CCL7, CCL19, CCL23, CCL25, IL-32). IrAE development was associated with on-treatment change in CCL23. PD-L1 expression was associated with the pre-treatment levels of TNFSF13B and the on-treatment change in CCL25. CD8+ TIL density was associated with the pre-treatment CXCL10 level, whereas NLR was correlated with pre-treatment levels of CCL13 and CCL17.

Conclusion: We identified several soluble immune mediators as pre-treatment and on-treatment biomarkers of survival in patients with NSCLC treated with ICI monotherapy. Some of these biomarkers were associated with other possible predictors, including irAE development, PD-L1 expression, CD8+ TIL density and NLR. Further large-scale studies are needed to establish biomarkers for patients with NSCLC who received ICI monotherapy.

背景:尽管ICI单药治疗具有良好的疗效,但大多数非小细胞肺癌(NSCLC)患者并无反应。因此,确定哪些患者能从 ICI 治疗中获得最佳疗效仍是一项挑战:在接受 ICI 单药治疗的 183 例晚期或复发性 NSCLC 患者中,我们分析了 110 例可获得治疗前和治疗后血浆样本的患者。在开始接受 ICI 治疗时和 6 周后,我们测定了 73 种可溶性免疫介质。为了找出有用的生物标志物,我们分析了可溶性免疫介质在治疗前和治疗中的水平变化与患者生存期的关系。我们还分析了治疗前或治疗中生物标志物与irAE发展、PD-L1表达、CD8+ TIL密度以及中性粒细胞与淋巴细胞比值(NLR)的关系:单变量分析显示,治疗前生物标志物包括6种免疫介质,而治疗中生物标志物包括8种免疫介质。多变量分析显示,治疗前生物标志物包括4种免疫介质(CCL19、CCL21、CXCL5、CXCL10),而治疗中生物标志物包括5种免疫介质(CCL7、CCL19、CCL23、CCL25、IL-32)。IrAE 的发生与治疗期间 CCL23 的变化有关。PD-L1 的表达与治疗前 TNFSF13B 的水平和治疗中 CCL25 的变化有关。CD8+ TIL密度与治疗前的CXCL10水平相关,而NLR与治疗前的CCL13和CCL17水平相关:我们发现了几种可溶性免疫介质,它们是接受 ICI 单药治疗的 NSCLC 患者治疗前和治疗中生存的生物标志物。其中一些生物标志物与其他可能的预测因子相关,包括irAE的发展、PD-L1的表达、CD8+ TIL密度和NLR。需要进一步开展大规模研究,为接受 ICI 单药治疗的 NSCLC 患者建立生物标志物。
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引用次数: 0
High proportion of PD-1 and CD39 positive CD8+ tissue resident T lymphocytes correlates with better clinical outcome in resected human oesophageal adenocarcinoma. 在切除的人类食管腺癌中,PD-1 和 CD39 阳性 CD8+ 组织常驻 T 淋巴细胞的高比例与更好的临床预后相关。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1007/s00262-024-03799-y
Samuel L Hill, Gessa Sugiyarto, Jack Harrington, Edward James, Timothy J Underwood, Tim Elliott

Objective: To understand the CD8+ tumour infiltrating lymphocyte (TIL) compartment of oesophageal adenocarcinoma (OAC) with regards to markers of lymphocyte exhaustion, tissue residency and to identify possible reasons behind differential responses to therapy.

Design: Tumour samples from 44 patients undergoing curative resection for OAC were assessed by flow cytometry for presence of antigen-experienced TILs and markers of activation and exhaustion. Populations of PD-1 and CD39 positive OAC TILs were sorted, and bulk RNA sequencing undertaken using a modified SmartSeq2 protocol. Flow cytometric assessment of functionality was completed.

Results: A higher proportion of antigen experienced CD8+ OAC TILs was associated with improved survival following surgery; while, high double positivity (DP) for PD-1 and CD39 among these TILs also correlated significantly with outcome. These DP TILs possess a minority population which is positive for the markers of exhaustion TIM3 and LAG3. Transcriptomic assessment of the PD-1 and CD39 DP TILs demonstrated enrichment for a tissue resident memory T lymphocyte (TRM) phenotype associated with improved survival in other cancers, reinforced by positivity for the canonical TRM marker CD103 by flow cytometry. This population demonstrated maintained functional capacity both in their transcriptomic profile, and on flow cytometric assessment, as well as preserved proliferative capacity.

Conclusion: Resected OAC are variably infiltrated by PD-1 and CD39 DP TILs, an abundance of which among lymphocytes is associated with improved survival. This DP population has an increased, but still modest, frequency of TIM3 and LAG3 positivity compared to DN, and is in keeping with a functionally competent TRM phenotype.

目的了解食管腺癌(OAC)CD8+肿瘤浸润淋巴细胞(TIL)区系的淋巴细胞衰竭标志物和组织驻留情况,并确定不同治疗反应背后的可能原因:设计:通过流式细胞术评估了44例接受根治性切除术的食管腺癌患者的肿瘤样本中抗原经验丰富的TIL以及活化和衰竭标记物的存在情况。对 PD-1 和 CD39 阳性的 OAC TILs 群体进行分拣,并使用改良的 SmartSeq2 方案进行批量 RNA 测序。完成了流式细胞术功能评估:结果:抗原经验丰富的 CD8+ OAC TILs 比例越高,术后生存率越高;同时,这些 TILs 的 PD-1 和 CD39 双阳性 (DP) 也与预后有显著相关性。这些双阳性 TIL 中的少数群体对衰竭标记物 TIM3 和 LAG3 呈阳性。对 PD-1 和 CD39 DP TIL 的转录组学评估显示,组织常驻记忆 T 淋巴细胞(TRM)表型的富集与其他癌症生存率的提高有关,流式细胞术显示的典型 TRM 标记 CD103 阳性则进一步证实了这一点。这一群体在其转录组图谱和流式细胞术评估中都显示出了维持功能的能力,并保留了增殖能力:结论:切除的 OAC 会受到 PD-1 和 CD39 DP TIL 的不同程度浸润,淋巴细胞中这种 DP TIL 的丰富程度与生存率的提高有关。与 DN 相比,这种 DP 群体的 TIM3 和 LAG3 阳性率更高,但仍不高,而且符合有功能能力的 TRM 表型。
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引用次数: 0
Impaired TGF-β signaling via AHNAK family mutations elicits an esophageal cancer subtype with sensitivities to genotoxic therapy and immunotherapy. 通过AHNAK家族突变导致的TGF-β信号传导受损会诱发一种对基因毒性疗法和免疫疗法敏感的食管癌亚型。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1007/s00262-024-03798-z
Zihang Mai, Luo Kongjia, Xinye Wang, Xiuying Xie, Lanlan Pang, Hong Yang, Jing Wen, Jianhua Fu

Background: Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear.

Methods: Here, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041.

Results: A two-gene (AHNAK and AHNAK2) mutation signature was identified to define the "AHNAK1/2-mutant" cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-β and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities to cisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25). The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients.

Conclusion: Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.

背景:基因组不稳定性(GI)是食管鳞状细胞癌(ESCC)的一个特征,而影响GI的因素仍不清楚。方法:在此,我们以201份ESCC样本为基础,旨在描述代表GI特定机制的基因组事件的特征,并在患者、单细胞和癌细胞系水平验证我们的发现,包括NCT04006041试验中新生成的多组学数据集:结果:确定了一个双基因(AHNAK和AHNAK2)突变特征,从而定义了 "AHNAK1/2突变 "癌症亚型。单细胞辅助多组学分析表明,该亚型具有较高的新抗原负荷、活跃的抗原呈递和熟练的CD8 + T细胞浸润,这在泛癌水平上得到了验证。从机理上讲,AHNAK1/2突变型ESCC的特点是对TGF-β的反应受损和替代性末端连接修复(Alt-EJ)效率低下,这可能会促进GI。在ESCC细胞系中敲除AHNAK会导致更多的Alt-EJ事件,并增加对顺铂的敏感性。此外,这两个基因特征还能准确预测各种临床环境中对DNA损伤疗法的更好反应(HR≈0.25)。在接受新辅助免疫疗法治疗的 ESCC 中,该双基因特征预测了更高的 pCR 率。最后,我们建立了一个分子分类方案,该方案在ESCC患者预后分层方面优于已有的分子分型模型:我们的研究拓展了我们对AHNAK家族在促进GI和选择ESCC治疗应答者方面的认识。
{"title":"Impaired TGF-β signaling via AHNAK family mutations elicits an esophageal cancer subtype with sensitivities to genotoxic therapy and immunotherapy.","authors":"Zihang Mai, Luo Kongjia, Xinye Wang, Xiuying Xie, Lanlan Pang, Hong Yang, Jing Wen, Jianhua Fu","doi":"10.1007/s00262-024-03798-z","DOIUrl":"10.1007/s00262-024-03798-z","url":null,"abstract":"<p><strong>Background: </strong>Genome instability (GI) is a hallmark of esophageal squamous cell carcinoma (ESCC) while factors affecting GI remain unclear.</p><p><strong>Methods: </strong>Here, we aimed to characterize genomic events representing specific mechanisms of GI based on 201 ESCC samples and validated our findings at the patient, single-cell and cancer cell-line levels, including a newly generated multi-omics dataset of the trial NCT04006041.</p><p><strong>Results: </strong>A two-gene (AHNAK and AHNAK2) mutation signature was identified to define the \"AHNAK1/2-mutant\" cancer subtype. Single-cell-assisted multi-omics analysis showed that this subtype had a higher neoantigen load, active antigen presentation, and proficient CD8 + T cell infiltrations, which were validated at pan-cancer levels. Mechanistically, AHNAK1/2-mutant ESCC was characterized by impaired response of TGF-β and the inefficient alternative end-join repair (Alt-EJ) that might promote GI. Knockdown of AHNAK in ESCC cell lines resulted in more Alt-EJ events and increased sensitivities to cisplatin. Furthermore, this two-gene signature accurately predicted better responses to DNA-damaging therapy in various clinical settings (HR ≈ 0.25). The two-gene signature predicted higher pCR rates in ESCCs receiving neoadjuvant immunotherapy-involved treatment. Finally, a molecular classification scheme was built and outperformed established molecular typing models in the prognosis stratification of ESCC patients.</p><p><strong>Conclusion: </strong>Our study extended our understanding of the AHNAK family in promoting GI and selecting treatment responders of ESCC.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 11","pages":"225"},"PeriodicalIF":4.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Distribution characteristics of immune infiltration and lymphovascular invasion in patients with breast cancer skin recurrence. 乳腺癌皮肤复发患者免疫浸润和淋巴管侵犯的分布特征
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1007/s00262-024-03783-6
Danyang Zhou, Mei Li, Wei Wu, Ying Wu, Qiaohong Nong, Shusen Wang, Ruoxi Hong

Background: To assess the distribution characteristics of immune infiltration and lymphovascular invasion in breast cancer skin recurrence patients.

Methods: We retrospectively analyzed the clinicopathological data of patients who underwent radical surgery for primary breast cancer and experienced skin recurrence between January 2001 and April 2019. Immune and lymphovascular biomarkers were quantified in primary breast cancers, skin lesions and visceral metastatic lesions. Differences in biomarkers distribution between matched tissues were statistically analyzed using the Wilcoxon signed-rank test and Kruskal-Wallis one-way ANOVA.

Results: A total of 71 female breast cancer patients were reviewed in this study. Our study found that the expression levels of various lymphocyte immune markers in primary tumor specimens were higher than those in skin recurrences. The expression of CD8, CD57 and CD31 in primary breast cancer was higher than those in the skin. Compared to visceral metastatic lesions, D2-40 was highly expressed in the skin, while CD8 tended to decrease. In the skin specimens, the expression of CD8 (P < 0.001), FOXP3 (P = 0.006) and CD68 (P < 0.001) in the intratumoral area was higher, while the expression of CD57 (P < 0.001) was higher in the peritumoral area. Analyzing specimens from the same patient at different time points of skin progression, it was found that the expression of peritumoral CD4 decreased (P = 0.044) as the disease progressed. The low expression of D2-40 and CD163 in the skin lesions suggested a decrease in DFS.

Conclusion: The immune microenvironment of breast cancer skin recurrence may be in a state of suppression, and this suppression may intensify with disease progression. The pattern of skin recurrence may be more inclined toward lymphatic invasion. Our study provides new insights into the biological behaviors of this disease and its response to immunotherapy.

背景:评估乳腺癌皮肤复发患者免疫浸润和淋巴管侵犯的分布特征:评估乳腺癌皮肤复发患者免疫浸润和淋巴管侵犯的分布特征:我们回顾性分析了 2001 年 1 月至 2019 年 4 月间接受原发性乳腺癌根治术并出现皮肤复发的患者的临床病理数据。对原发性乳腺癌、皮肤病变和内脏转移病变中的免疫和淋巴管生物标志物进行了量化。采用Wilcoxon符号秩检验和Kruskal-Wallis单因素方差分析对匹配组织间的生物标志物分布差异进行统计分析:本研究共回顾性分析了71例女性乳腺癌患者。研究发现,原发肿瘤标本中各种淋巴细胞免疫标志物的表达水平高于皮肤复发标本。CD8、CD57和CD31在原发性乳腺癌中的表达高于皮肤中的表达。与内脏转移病灶相比,D2-40在皮肤中的表达量较高,而CD8则呈下降趋势。在皮肤标本中,CD8(P 结论:CD8在皮肤标本中的表达高于CD31在皮肤标本中的表达:乳腺癌皮肤复发的免疫微环境可能处于抑制状态,这种抑制可能会随着疾病的进展而加剧。皮肤复发的模式可能更倾向于淋巴侵袭。我们的研究为了解这种疾病的生物学行为及其对免疫疗法的反应提供了新的视角。
{"title":"Distribution characteristics of immune infiltration and lymphovascular invasion in patients with breast cancer skin recurrence.","authors":"Danyang Zhou, Mei Li, Wei Wu, Ying Wu, Qiaohong Nong, Shusen Wang, Ruoxi Hong","doi":"10.1007/s00262-024-03783-6","DOIUrl":"10.1007/s00262-024-03783-6","url":null,"abstract":"<p><strong>Background: </strong>To assess the distribution characteristics of immune infiltration and lymphovascular invasion in breast cancer skin recurrence patients.</p><p><strong>Methods: </strong>We retrospectively analyzed the clinicopathological data of patients who underwent radical surgery for primary breast cancer and experienced skin recurrence between January 2001 and April 2019. Immune and lymphovascular biomarkers were quantified in primary breast cancers, skin lesions and visceral metastatic lesions. Differences in biomarkers distribution between matched tissues were statistically analyzed using the Wilcoxon signed-rank test and Kruskal-Wallis one-way ANOVA.</p><p><strong>Results: </strong>A total of 71 female breast cancer patients were reviewed in this study. Our study found that the expression levels of various lymphocyte immune markers in primary tumor specimens were higher than those in skin recurrences. The expression of CD8, CD57 and CD31 in primary breast cancer was higher than those in the skin. Compared to visceral metastatic lesions, D2-40 was highly expressed in the skin, while CD8 tended to decrease. In the skin specimens, the expression of CD8 (P < 0.001), FOXP3 (P = 0.006) and CD68 (P < 0.001) in the intratumoral area was higher, while the expression of CD57 (P < 0.001) was higher in the peritumoral area. Analyzing specimens from the same patient at different time points of skin progression, it was found that the expression of peritumoral CD4 decreased (P = 0.044) as the disease progressed. The low expression of D2-40 and CD163 in the skin lesions suggested a decrease in DFS.</p><p><strong>Conclusion: </strong>The immune microenvironment of breast cancer skin recurrence may be in a state of suppression, and this suppression may intensify with disease progression. The pattern of skin recurrence may be more inclined toward lymphatic invasion. Our study provides new insights into the biological behaviors of this disease and its response to immunotherapy.</p>","PeriodicalId":9595,"journal":{"name":"Cancer Immunology, Immunotherapy","volume":"73 11","pages":"223"},"PeriodicalIF":4.6,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11377393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142131966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The short-term efficacy of neoadjuvant SOX versus SOX plus immune checkpoint inhibitor following laparoscopic gastrectomy for locally advanced gastric cancer: a multicenter retrospective cohort study in China. 中国一项多中心回顾性队列研究:局部晚期胃癌腹腔镜胃切除术后新辅助SOX与SOX加免疫检查点抑制剂的短期疗效比较。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1007/s00262-024-03802-6
Hao Cui, Yongpu Yang, Liqiang Song, Zhen Yuan, Linde Sun, Jiajun Du, Yuyuan Lu, Ning Ning, Jianxin Cui, Yan Shi, Lin Chen, Bo Wei

Background: This study aims to evaluate the short-term efficacy for locally advanced gastric cancer (LAGC) who accepted laparoscopic gastrectomy (LG) after neoadjuvant SOX versus SOX plus immune checkpoint inhibitors (ICIs).

Methods: LAGC patients who accepted LG after neoadjuvant SOX (SOX-LG, n = 169) and SOX plus ICIs (SOX + ICIs-LG, n = 140) in three medical centers between Jan 2020 and Mar 2024 were analyzed. We compared the tumor regression, treatment-related adverse events (TRAEs), perioperative safety between two groups, and explored the risk factors of postoperative complications (POCs) for LG after neoadjuvant therapy.

Results: The baseline characteristics were comparable between two groups (P > 0.05). SOX + ICIs-LG group acquired a higher proportion of objective response (63.6% vs. 46.7%, P = 0.003), major pathological response (43.6% vs. 31.4%, P = 0.001), and pathological complete response (17.9% vs. 9.5%, P = 0.030). There were no significant differences in the TRAEs rates, operation time, R0 resection, retrieved lymph nodes, postoperative first flatus, and hospitalized days, overall and severe POCs between two groups (P > 0.05). Patients in the SOX-ICIs-LG group had lower estimated blood loss (EBL) compared with SOX-LG (P = 0.001). Multivariate analysis showed that more EBL (P = 0.003) and prognostic nutritional index (PNI) < 40 (P = 0.005) were independent risk factors of POCs for LG after neoadjuvant therapy.

Conclusion: Neoadjuvant SOX plus ICIs brings better tumor regression and similar TRAEs compared with SOX alone for LAGC. SOX + ICIs-LG is safe and feasible to conduct with less EBL. Surgeons should focus on the perioperative management to control POCs for patients with PNI < 40 and more EBL.

研究背景本研究旨在评估接受腹腔镜胃切除术(LG)的局部晚期胃癌(LAGC)患者在新辅助SOX与SOX加免疫检查点抑制剂(ICIs)治疗后的短期疗效:分析了2020年1月至2024年3月期间在三家医疗中心接受新辅助SOX(SOX-LG,n = 169)和SOX加ICIs(SOX + ICIs-LG,n = 140)后腹腔镜胃切除术(LG)的LAGC患者。我们比较了两组患者的肿瘤消退情况、治疗相关不良事件(TRAEs)、围手术期安全性,并探讨了新辅助治疗后LG术后并发症(POCs)的风险因素:结果:两组患者的基线特征具有可比性(P>0.05)。SOX+ICIs-LG组获得客观反应(63.6% vs. 46.7%,P = 0.003)、主要病理反应(43.6% vs. 31.4%,P = 0.001)和病理完全反应(17.9% vs. 9.5%,P = 0.030)的比例更高。两组患者的TRAEs率、手术时间、R0切除率、淋巴结取回率、术后首次排便率、住院天数、总体POCs和严重POCs无明显差异(P > 0.05)。与SOX-LG组相比,SOX-ICIs-LG组患者的估计失血量(EBL)更低(P = 0.001)。多变量分析显示,EBL(P = 0.003)和预后营养指数(PNI)更高:与单用 SOX 治疗 LAGC 相比,新辅助 SOX 加 ICIs 能带来更好的肿瘤消退效果和相似的 TRAEs。SOX+ICIs-LG安全可行,EBL较低。外科医生应重视围手术期管理,以控制 PNI 患者的 POCs
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引用次数: 0
Oncolytic virotherapy augments self-maintaining natural killer cell line cytotoxicity against neuroblastoma. 肿瘤溶解病毒疗法增强了自维持自然杀伤细胞系对神经母细胞瘤的细胞毒性。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1007/s00262-024-03818-y
Colin H Quinn, Janet R Julson, Hooper R Markert, Nazia Nazam, Swatika Butey, Jerry E Stewart, Jennifer C Coleman, James M Markert, Jianmei W Leavenworth, Elizabeth A Beierle

Background: Neuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of pediatric cancer related deaths. Targeting neuroblastoma with immunotherapies has proven challenging due to a paucity of immune cells in the tumor microenvironment and the release of immunosuppressive cytokines by neuroblastoma tumor cells. We hypothesized that combining an oncolytic Herpes Simplex Virus (oHSV) with natural killer (NK) cells might overcome these barriers and incite tumor cell death.

Methods: We utilized MYCN amplified and non-amplified neuroblastoma cell lines, the IL-12 expressing oHSV, M002, and the human NK cell line, NK-92 MI. We assessed the cytotoxicity of NK cells against neuroblastoma with and without M002 infection, the effects of M002 on NK cell priming, and the impact of M002 and priming on the migratory capacity and CD107a expression of NK cells. To test clinical applicability, we then investigated the effects of M002 and NK cells on neuroblastoma in vivo.

Results: NK cells were more attracted to neuroblastoma cells that were infected with M002. There was an increase in neuroblastoma cell death with the combination treatment of M002 and NK cells both in vitro and in vivo. Priming the NK cells enhanced their cytotoxicity, migratory capacity and CD107a expression.

Conclusions: To the best of our knowledge, these investigations are the first to demonstrate the effects of an oncolytic virus combined with self-maintaining NK cells in neuroblastoma and the priming effect of neuroblastoma on NK cells. The current studies provide a deeper understanding of the relation between NK cells and neuroblastoma and these data suggest that oHSV increases NK cell cytotoxicity towards neuroblastoma.

背景:神经母细胞瘤是儿童最常见的颅外实体瘤,占儿童癌症相关死亡人数的 15%。由于肿瘤微环境中免疫细胞稀少以及神经母细胞瘤肿瘤细胞释放免疫抑制细胞因子,用免疫疗法靶向神经母细胞瘤已被证明具有挑战性。我们假设,将溶瘤性单纯疱疹病毒(oHSV)与自然杀伤细胞(NK)相结合,可能会克服这些障碍并诱导肿瘤细胞死亡:我们利用了 MYCN 扩增和非扩增的神经母细胞瘤细胞系、表达 IL-12 的 oHSV M002 和人类 NK 细胞系 NK-92 MI。我们评估了感染和未感染 M002 的 NK 细胞对神经母细胞瘤的细胞毒性、M002 对 NK 细胞引物的影响,以及 M002 和引物对 NK 细胞迁移能力和 CD107a 表达的影响。为了测试临床应用性,我们随后研究了M002和NK细胞对体内神经母细胞瘤的影响:结果:NK细胞更容易被感染了M002的神经母细胞瘤细胞吸引。M002和NK细胞在体外和体内的联合处理增加了神经母细胞瘤细胞的死亡。对NK细胞进行引物处理可增强其细胞毒性、迁移能力和CD107a表达:据我们所知,这些研究首次证明了溶瘤病毒与自我维持的 NK 细胞结合对神经母细胞瘤的影响,以及神经母细胞瘤对 NK 细胞的引诱作用。目前的研究加深了人们对 NK 细胞与神经母细胞瘤之间关系的理解,这些数据表明 oHSV 增加了 NK 细胞对神经母细胞瘤的细胞毒性。
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引用次数: 0
Immune microenvironmental heterogeneity according to tumor DNA methylation phenotypes in microsatellite instability-high colorectal cancers. 根据微卫星不稳定性高的结直肠癌中肿瘤 DNA 甲基化表型的免疫微环境异质性。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1007/s00262-024-03805-3
Jung Ho Kim, Jiyun Hong, Ji Ae Lee, Minsun Jung, Eunwoo Choi, Nam-Yun Cho, Gyeong Hoon Kang, Sangwoo Kim

The detailed association between tumor DNA methylation, including CpG island methylation, and tumor immunity is poorly understood. CpG island methylator phenotype (CIMP) is observed typically in sporadic colorectal cancers (CRCs) with microsatellite instability-high (MSI-H). Here, we investigated the differential features of the tumor immune microenvironment according to CIMP status in MSI-H CRCs. CIMP-high (CIMP-H) or CIMP-low/negative (CIMP-L/0) status was determined using MethyLight assay in 133 MSI-H CRCs. All MSI-H CRCs were subjected to digital pathology-based quantification of CD3 + /CD8 + /CD4 + /FoxP3 + /CD68 + /CD204 + /CD177 + tumor-infiltrating immune cells using whole-slide immunohistochemistry. Programmed death-ligand 1 (PD-L1) immunohistochemistry was evaluated using the tumor proportion score (TPS) and combined positive score (CPS). Representative cases were analyzed using whole-exome and RNA-sequencing. In 133 MSI-H CRCs, significantly higher densities of CD8 + tumor-infiltrating lymphocytes (TILs) were observed in CIMP-H tumors compared with CIMP-L/0 tumors. PD-L1 TPS and CPS in CIMP-H tumors were higher than in CIMP-L/0 tumors. Next-generation sequencing revealed that, compared with CIMP-L/0 tumors, CIMP-H tumors had higher fractions of CD8 + T cells/cytotoxic lymphocytes, higher cytolytic activity scores, and activated immune-mediated cell killing pathways. In contrast to CIMP-L/0 tumors, most CIMP-H tumors were identified as consensus molecular subtype 1, an immunogenic transcriptomic subtype of CRC. However, there were no differences in tumor mutational burden (TMB) between CIMP-H and CIMP-L/0 tumors in MSI-H CRCs. In conclusion, CIMP-H is associated with abundant cytotoxic CD8 + TILs and PD-L1 overexpression independent of TMB in MSI-H CRCs, suggesting that CIMP-H tumors represent a typical immune-hot subtype and are optimal candidates for immunotherapy in MSI-H tumors.

人们对肿瘤 DNA 甲基化(包括 CpG 岛甲基化)与肿瘤免疫之间的详细关系知之甚少。CpG岛甲基化表型(CIMP)通常出现在微卫星不稳定性高(MSI-H)的散发性结直肠癌(CRC)中。在此,我们研究了微卫星不稳定性高(MSI-H)结直肠癌中根据 CIMP 状态不同的肿瘤免疫微环境特征。在133例MSI-H型CRC中使用MethyLight检测法确定CIMP-高(CIMP-H)或CIMP-低/阴性(CIMP-L/0)状态。所有 MSI-H CRC 均采用全切片免疫组织化学方法,对 CD3 + /CD8 + /CD4 + /FoxP3 + /CD68 + /CD204 + /CD177 + 肿瘤浸润免疫细胞进行基于数字病理学的定量分析。程序性死亡配体 1(PD-L1)免疫组化采用肿瘤比例评分(TPS)和联合阳性评分(CPS)进行评估。采用全外显子组和 RNA 序列对代表性病例进行了分析。在133例MSI-H型CRC中,与CIMP-L/0型肿瘤相比,CIMP-H型肿瘤中CD8 +肿瘤浸润淋巴细胞(TIL)的密度明显更高。CIMP-H肿瘤中的PD-L1 TPS和CPS高于CIMP-L/0肿瘤。下一代测序显示,与CIMP-L/0肿瘤相比,CIMP-H肿瘤的CD8 + T细胞/细胞毒性淋巴细胞比例更高,细胞溶解活性评分更高,免疫介导的细胞杀伤通路被激活。与 CIMP-L/0 肿瘤相比,大多数 CIMP-H 肿瘤被鉴定为共识分子亚型 1,即 CRC 的免疫原性转录组亚型。然而,在MSI-H型CRC中,CIMP-H和CIMP-L/0肿瘤的肿瘤突变负荷(TMB)并无差异。总之,在MSI-H型CRC中,CIMP-H与丰富的细胞毒性CD8 + TILs和PD-L1过表达相关,与TMB无关,这表明CIMP-H肿瘤代表了一种典型的免疫热亚型,是MSI-H肿瘤免疫疗法的最佳候选者。
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引用次数: 0
Stat3-mediated Atg7 expression regulates anti-tumor immunity in mouse melanoma. Stat3 介导的 Atg7 表达调节小鼠黑色素瘤的抗肿瘤免疫。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-09-05 DOI: 10.1007/s00262-024-03804-4
Sarah M Zimmerman, Erin Suh, Sofia R Smith, George P Souroullas

Epigenetic modifications to DNA and chromatin control oncogenic and tumor-suppressive mechanisms in melanoma. Ezh2, the catalytic component of the Polycomb Repressive Complex 2 (PRC2), which mediates methylation of lysine 27 on histone 3 (H3K27me3), can regulate both melanoma initiation and progression. We previously found that mutant Ezh2Y641F interacts with the immune regulator Stat3 and together they affect anti-tumor immunity. However, given the numerous downstream targets and pathways affected by Ezh2, many mechanisms that determine its oncogenic activity remain largely unexplored. Using genetically engineered mouse models, we further investigated the role of pathways downstream of Ezh2 in melanoma carcinogenesis and identified significant enrichment in several autophagy signatures, along with increased expression of autophagy regulators, such as Atg7. In this study, we investigated the effect of Atg7 on melanoma growth and tumor immunity within the context of a wild-type or Ezh2Y641F epigenetic state. We found that the Atg7 locus is controlled by multiple Ezh2 and Stat3 binding sites, Atg7 expression is dependent on Stat3 expression, and that deletion of Atg7 slows down melanoma cell growth in vivo, but not in vitro. Atg7 deletion also results in increased CD8 + T cells in Ezh2Y641F melanomas and reduced myelosuppressive cell infiltration in the tumor microenvironment, particularly in Ezh2WT melanomas, suggesting a strong immune system contribution in the role of Atg7 in melanoma progression. These findings highlight the complex interplay between genetic mutations, epigenetic regulators, and autophagy in shaping tumor immunity in melanoma.

DNA和染色质的表观遗传修饰控制着黑色素瘤的致癌和抑瘤机制。Ezh2是多聚核抑制复合体2(PRC2)的催化元件,它介导组蛋白3上赖氨酸27的甲基化(H3K27me3),可调控黑色素瘤的发生和发展。我们以前曾发现,突变体Ezh2Y641F与免疫调节剂Stat3相互作用,共同影响抗肿瘤免疫。然而,由于受Ezh2影响的下游靶点和通路众多,决定其致癌活性的许多机制在很大程度上仍未被探索。利用基因工程小鼠模型,我们进一步研究了 Ezh2 下游通路在黑色素瘤癌变中的作用,发现了多个自噬特征的显著富集,以及 Atg7 等自噬调节因子的表达增加。在本研究中,我们研究了野生型或 Ezh2Y641F 表观遗传学状态下 Atg7 对黑色素瘤生长和肿瘤免疫的影响。我们发现,Atg7基因座受多个Ezh2和Stat3结合位点控制,Atg7的表达依赖于Stat3的表达。Atg7缺失还导致Ezh2Y641F黑色素瘤中CD8 + T细胞增加,肿瘤微环境中骨髓抑制细胞浸润减少,尤其是在Ezh2WT黑色素瘤中,这表明Atg7在黑色素瘤进展过程中的作用与免疫系统密切相关。这些发现突显了基因突变、表观遗传调控因子和自噬在黑色素瘤中影响肿瘤免疫的复杂相互作用。
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引用次数: 0
Preclinical development of a novel CCR8/CTLA-4 bispecific antibody for cancer treatment by disrupting CTLA-4 signaling on CD8 T cells and specifically depleting tumor-resident Tregs. 新型 CCR8/CTLA-4 双特异性抗体的临床前开发,通过破坏 CD8 T 细胞上的 CTLA-4 信号传导和特异性消耗肿瘤驻留的 Tregs 来治疗癌症。
IF 4.6 2区 医学 Q2 IMMUNOLOGY Pub Date : 2024-08-09 DOI: 10.1007/s00262-024-03794-3
Cuicui Guo, Xiaodong Dai, Yulei Du, Xiumei Xiong, Xun Gui

Anti-CTLA-4 antibodies faced challenges due to frequent adverse events and limited efficacy, which spurred the exploration of next-generation CTLA-4 therapeutics to balance regulatory T cells (Tregs) depletion and CD8 T cells activation. CCR8, identified primarily on tumor-infiltrating Tregs, has become a target of interest due to the anti-tumor effects demonstrated by CCR8 antibody-mediated Tregs depletion. Single-cell RNA sequencing analysis reveals that CCR8-positive Tregs constitute a small subset, with concurrent expression of CCR8 and CTLA-4. Consequently, we proposed a novel bispecific antibody targeting CCR8 and CTLA-4 that had the potential to enhance T cell activation while selectively depleting intratumor Tregs. The candidate molecule 2MW4691 was developed in a tetravalent symmetric format, maintaining a strong binding affinity for CCR8 while exhibiting relatively weaker CTLA-4 binding. This selective binding ability allowed 2MW4691 to target and deplete tumor-infiltrating Tregs with higher specificity. In vitro assays verified the antibody's capacity for antibody-dependent cellular cytotoxicity (ADCC) to Tregs with high level of CTLA-4 expression, but not CD8 T cells with relatively low level of CTLA-4 on cell surface. Also, 2MW4691 inhibited the CTLA-4 pathway and enhanced T cell activation. The in vivo therapeutic efficacy of 2MW4691 was further demonstrated using hCCR8 or hCTLA-4 humanized mouse models and hCCR8/hCTLA-4 double knock-in mouse models. In cynomolgus monkeys, 2MW4691 was well-tolerated, exhibited the anticipated pharmacokinetic profile, and had a minimal impact on the peripheral T cell population. The promising preclinical results supported the further evaluation of 2MW4691 as a next-generation Treg-based therapeutics in clinical trials.

抗CTLA-4抗体因不良反应频发和疗效有限而面临挑战,这促使人们探索下一代CTLA-4疗法,以平衡调节性T细胞(Tregs)消耗和CD8 T细胞激活。CCR8主要在肿瘤浸润性Tregs上被发现,由于CCR8抗体介导的Tregs耗竭具有抗肿瘤作用,CCR8已成为人们关注的靶点。单细胞 RNA 测序分析表明,CCR8 阳性的 Tregs 构成了一个小的亚群,同时表达 CCR8 和 CTLA-4。因此,我们提出了一种靶向CCR8和CTLA-4的新型双特异性抗体,它有可能在增强T细胞活化的同时选择性地消耗肿瘤内的Tregs。候选分子 2MW4691 采用四价对称形式开发,与 CCR8 的结合亲和力很强,而与 CTLA-4 的结合力相对较弱。这种选择性结合能力使 2MW4691 能够以更高的特异性靶向并清除肿瘤浸润性集落细胞。体外实验验证了该抗体对高水平 CTLA-4 表达的 Tregs 的抗体依赖性细胞毒性(ADCC)能力,但对细胞表面 CTLA-4 水平相对较低的 CD8 T 细胞的抗体依赖性细胞毒性(ADCC)能力却没有验证。此外,2MW4691还能抑制CTLA-4通路,增强T细胞活化。使用 hCCR8 或 hCTLA-4 人源化小鼠模型和 hCCR8/hCTLA-4 双基因敲入小鼠模型进一步证实了 2MW4691 的体内疗效。在猴体内,2MW4691的耐受性良好,表现出预期的药代动力学特征,并且对外周T细胞群的影响极小。充满希望的临床前研究结果支持在临床试验中进一步评估 2MW4691 作为基于 Treg 的下一代疗法。
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引用次数: 0
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Cancer Immunology, Immunotherapy
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